title: A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors.
abstract: In human trials certain heat shock protein 90 (Hsp90) inhibitors, including 17-DMAG and NVP-AUY922, have caused visual disorders indicative of retinal dysfunction; others such as 17-AAG and ganetespib have not. To understand these safety profile differences we evaluated histopathological changes and exposure profiles of four Hsp90 inhibitors, with or without clinical reports of adverse ocular effects, using a rat retinal model. Retinal morphology, Hsp70 expression (a surrogate marker of Hsp90 inhibition), apoptotic induction and pharmacokinetic drug exposure analysis were examined in rats treated with the ansamycins 17-DMAG and 17-AAG, or with the second-generation compounds NVP-AUY922 and ganetespib. Both 17-DMAG and NVP-AUY922 induced strong yet restricted retinal Hsp70 up-regulation and promoted marked photoreceptor cell death 24h after the final dose. In contrast, neither 17-AAG nor ganetespib elicited photoreceptor injury. When the relationship between drug distribution and photoreceptor degeneration was examined, 17-DMAG and NVP-AUY922 showed substantial retinal accumulation, with high retina/plasma (R/P) ratios and slow elimination rates, such that 51% of 17-DMAG and 65% of NVP-AUY922 present at 30 min post-injection were retained in the retina 6h post-dose. For 17-AAG and ganetespib, retinal elimination was rapid (90% and 70% of drugs eliminated from the retina at 6h, respectively) which correlated with lower R/P ratios. These findings indicate that prolonged inhibition of Hsp90 activity in the eye results in photoreceptor cell death. Moreover, the results suggest that the retina/plasma exposure ratio and retinal elimination rate profiles of Hsp90 inhibitors, irrespective of their chemical class, may predict for ocular toxicity potential.
authors.affiliation: Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USA. Electronic address: DZhou@syntapharma.com.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Josephine
authors.initials: J
authors.lastname: Ye
authors.forename: Weiwen
authors.initials: W
authors.lastname: Ying
authors.forename: Luisa Shin
authors.initials: LS
authors.lastname: Ogawa
authors.forename: Takayo
authors.initials: T
authors.lastname: Inoue
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tatsuta
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Wada
authors.forename: Keizo
authors.initials: K
authors.lastname: Koya
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Bates
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sonderfan
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000633:toxicity; D008297:Male; D010786:Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012162:Retinal Degeneration / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin
keywords: Drug safety assessment; Hsp90 inhibitors; Predictive toxicology; Retinal degeneration; Rodent model; Visual impairment